Razine Drug Interactions

Effects of Other Drugs on Ranolazine: Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp).
CYP3A Inhibitors: Do not use Ranolazine with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) increases average steady-state plasma concentrations of ranolazine 3.2-fold.
Limit the dose of Ranolazine to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products. Diltiazem (180-360 mg daily) and verapamil (120 mg three times daily) increase ranolazine steady-state plasma concentration about 2-fold.
Weak CYP3A inhibitors such as simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers.
P-gp Inhibitors: Down-titrate Ranolazine based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine.
CYP3A and P-gp Inducers: Avoid co-administration of Ranolazine and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort. Rifampin (600 mg once daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95% by induction of CYP3A and, probably, P-gp.
CYP2D6 Inhibitors: The potent CYP2D6 inhibitor, paroxetine (20 mg once daily), increases ranolazine concentrations 1.2-fold. No dose adjustment of Ranolazine is required in patients treated with CYP2D6 inhibitors.
Digoxin: Digoxin (0.125 mg) does not significantly alter ranolazine levels.
Effects of Ranolazine on Other Drugs: In vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors. Ranolazine and its most abundant metabolites are not known to inhibit the metabolism of substrates of CYP 1A2, 2C8, 2C9, 2C19, or 2E1 in human liver microsomes, suggesting that ranolazine is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.
Drugs Metabolized by CYP3A: The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are each increased about 2-fold in healthy subjects receiving simvastatin (80 mg once daily) and Ranolazine (1000 mg twice daily). Dose adjustments of simvastatin are not required when Ranolazine is co-administered with simvastatin.
The pharmacokinetics of diltiazem is not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and Ranolazine 1000 mg twice daily.
Drugs Transported by P-gp: Ranolazine (1000 mg twice daily) causes a 1.5-fold elevation of digoxin plasma concentration. The dose of digoxin may have to be adjusted.
Drugs Metabolized by CYP2D6: Ranolazine or its metabolites partially inhibit CYPD6. There are no studies of concomitant use of Ranolazine with other drugs metabolized by CYP2D6, such as tricyclic antidepressants and antipsychotics, but lower doses of CYP2D6 substrates may be required.